Membrane-stabilizing activity

Regarding the proposed mechanisms of carvedilol antioxidative activity, membrane stabilization through the biophysical interaction of carvedilol with the membrane seems to be the most reliable one. However, a higher antioxidant activity of the metabolite SB 211475 leads to another explanation. In contrast to the parent carvedilol, SB 211475 has the active free radical scavenging phenolic hydroxyl, which is apparently responsible for its enhanced antioxidant activity. Thus, we may suggest that the in vivo antioxidant activity of carvedilol is due to its converting into active metabolites, which, for example, may be formed in the reactions with primary free radicals such as hydroxyl radicals. 

Many beta-adrenoceptor antagonists (beta-blockers) have been developed, and their adverse effects have been comprehensively reviewed (1). The spectmm of adverse effects is broadly similar for aU beta-blockers, despite differences in their pharmacological properties, notably cardioselectiv-ity, partial agonist activity, membrane-stabilizing activity, and lipid solnbUity (see Table 1). The inflnence of these properties is mentioned in the general discnssion when appropriate and is snmmarized at the end of the section. Individnal differences in toxicity are largely nnimportant bnt win be mentioned briefly. 

Drug Lipid solubility Cardioselectivity Partial agonist activity Membrane-Stabilizing activity... 

Local anesthetic activity Local anesthetic activity ( membrane stabilizing activity ) is a disadvantage when beta-blockers are used topically in the eye because it decreases protective reflexes and increases the risk of corneal ulceration. Local anesthetic effects are absent from timolol and several other beta-blockers. 

Note that the relative spatial arrangement of the phenyl, amine, and hydroxyl functionahties are identical for (R)-alprenolol and (5)-sotalol. In addition to P-blocking activities, some of these compounds also possess potent local anaesthetic activity (see Anesthetics). The membrane stabilizing activity, however, is not stereoselective and correlates directly with the partition coefficient (hydrophobicity) of the compound. 

Acebutolol. Acebutolol hydrochloride is a hydrophilic, cardioselective P-adrenoceptor blocker that has about 1/25 the potency of propranolol in this regard. The dmg has moderate ISA and weak membrane stabilizing activities. It is approved for the treatment of hypertension and ventricular arrhythmias, especially PVCs. Acebutolol should produce minimal depression of heart rate because of its ISA (32). 

Esmolol. Esmolol hydrochloride, an ultrashort acting cardioselective P ceptor blocker having no ISA or membrane stabilizing activity, is... 

Bopindolol is a long-acting, nonselective P-adrenoceptor blocker. It has mild membrane stabilizing activity and ISA. In vivo, the compound is hydrolyzed to its active metabohte. Because of this prodmg feature the onset of action is slower than other available P-adrenoceptor blockers. Preliminary pharmacokinetic studies indicate that the compound is weU absorbed, is 70% bioavailable, and peak plasma levels are achieved in about 2 h. Whereas its elimination half-life is 4—8 h, P-adrenoceptor blocking action (- 40%) is stiU apparent after 48 h. The dmg is being studied in hypertension, angina, and arrhythmias (43). 

Nadolol. Nadolol (Table 3) is a hydrophilic, nonselective -adrenoceptor blocking agent having no ISA and no membrane-stabilizing activity. It is useful for the treatment of hypertension and chronic stable exertional angina (98,99,108). 

Betaxolol hydrochloride is a lipophilic, cardioselective -adrenoceptor blocker having no ISA and Httie membrane-stabilizing activity. The dmg is as equieffective and equipotent as atenolol. It is well absorbed from the GI tract, but does not undergo extensive first-pass metaboHsm in the Hver. Its elimination half-Hfe is 15—20 h. It is metabolized in the Hver ( 84%) to two principal inactive metaboHtes and one minor active metaboHte. About 16% of the dmg is excreted unchanged urine. Excretion of the dmg is unchanged in patients having renal or Hver impairment (43). 

Bisoprolol fumarate is a long-acting, cardioselective -adrenoceptor blocker, and is the most potent cardioselective -adrenoceptor blocker available. Bisoprolol has no ISA. At high concentrations it has membrane-stabilizing activity. The dmg has a "balanced clearance", ie, half is excreted by the kidneys and half is eliminated by the Hver and its excretion is not affected by functional impairment of either organ. It is approved in Europe for hypertension and is being studied in angina (43). 

Bevantolol hydrochloride is a moderately lipophilic, long-acting, cardioselective -adrenoceptor blocker. It has no ISA but has membrane-stabilizing activity. The dmg is in use in Europe for the treatment of hypertension and angina. It is rapidly absorbed from the GI tract. Peak plasma levels occur in 1—2 h. It is metabolized extensively in the Hver to a metaboHte that has some ISA. It is excreted by the Hver and the kidneys and excretion is delayed in patients having kidney failure. 

Treatment of 2,6-dimethylaniline (121) with phosgene and triethylamine affords the corre-S]ionding isocyanate (122). Condensation of that reactive intermediate with N-isopropylpropyl-cne-1,3-diamine leads to formation of urea 123. This product, recainam (123), acts as membrane Stabilizing agent and thus exhibits both local anesthetic and antiarrhythmic activity [30]. 

Each of these properties may be exploited to some extent when prescribing a P-blocker, while others (membrane stabilization activity and ISA) are more of theoretical interest, with less relative value in clinical practice. For example, consider a patient with mild asthma, chronic obstructive... 

The correct ratio of lipid constituents is important to form stable liposomes. For instance, a reliable liposomal composition for encapsulating aqueous substances may contain molar ratios of lecithin cholesterol negatively charged phospholipid (e.g., phosphatidyl glycerol (PG)) of 0.9 1 0.1. A composition that is typical when an activated phosphatidylethanolamine (PE) derivative is included may contain molar ratios of phosphatidylcholine (PC) cholesterol PG derivatized PE of 8 10 1 1. Another typical composition using a maleimide derivative of PE without PG is PC male-imide-PE cholesterol of 85 15 50 (Friede et al., 1993). In general, to maintain membrane stability, the PE derivative should not exceed a concentration ratio of about l-10mol PE per lOOmol of total lipid. 

Enzyme containing Nation membranes prepared according to the proposed protocol have shown high specific activity and stability of immobilized glucose oxidase. As expected, the simplicity of preparation provided high reproducibility. When the same casting solution is used, the maximum deviation in membrane activity is <2%. This, however, is also the precision limit for kinetic investigations. 

Esmolol hydrochloride is a competitive p-adrenergic receptor antagonist it is selective for pT adrenoceptors. In contrast to pindolol, esmolol has little intrinsic sympathomimetic activity, and it differs from propranolol in that it lacks membrane stabilizing activity Of all of the p-adrenergic blocking drugs, this compound has the shortest duration of action because it is an ester, it is hydrolyzed rapidly by plasma esterases and must be used by the intravenous route Esmolol is approved only for the treatment of supraventricular arrhythmias... 

The short-acting / -agonists (Table 80-1) are the most effective broncho-dilators available. /J2-Adrenergic receptor stimulation activates adenyl cyclase, which produces an increase in intracellular cyclic adenosine monophosphate. This results in smooth muscle relaxation, mast cell membrane stabilization, and skeletal muscle stimulation. 

Red blood cell hemolysis Membrane stabilization Chloropromazine (not a receptor-mediated activity) Seeman and Weinstein, 1966... 

Platinum deposited on Nafion shows long lasting catalytic activity for methanol oxidation3i-32, because the membrane stabilizes Pt2+. which oxidize methanol. ... 

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